by Sanjay Gupta
This photograph of two thirteen-year-old boys—one vaccinated and one not—was taken in the early 1900s by Dr. Allan Warner of the Isolation Hospital at Leicester in the United Kingdom. It was part of a series of photographs by Warner that were published in the Atlas of Clinical Medicine, Surgery, and Pathology in 1901. Warner photographed a number of smallpox patients in order to study the disease. Both boys had been infected by the same smallpox source on the same day, but only one (on the right) had received a vaccination in infancy. Note that while the boy on the left is in the fully pustular stage, the boy on the right has had only two spots, which have aborted and have already scabbed. Apparently, the parents of the boy on the left were swept up by anti-vaccination fervor when they decided not to inoculate their child. SOURCE: THE JENNER TRUST. THE PHOTO IS PART OF A COLLECTION HOUSED AT DR. JENNER’S HOUSE, MUSEUM AND GARDEN IN GLOUCESTERSHIRE, ENGLAND. FOR MORE, GO TO JENNERMUSEUM.COM.
“The miracle is that the people came together and did it [ended the pandemic]. The magic is the science, but the miracle is the people,” Brilliant says. Smallpox was a unique germ in that it infected only humans. It didn’t have any other hosts, so exterminating it was easier once we had the vaccine against it. COVID, however, will be a virus we chase as it mutates and circulates in other animals. Until the world is fully vaccinated, there will always be customers for COVID.
Ask Dr. Brilliant what he thinks about anti-vaxxers and he’s quick to point out, amusingly, “Oh, you mean the people against cows?” Much of the vaccine avoidance among anti-vaxxers has stemmed from the notion that the only way to be protected from an illness is to contract a bit of the illness itself. Many people fear that vaccines will cause the illness against which they protect. But that’s the beauty of vaccines: They offer the protection without devastating illness. Today’s vaccines also have the benefits of modern science; they are exceedingly safe and rigorously tested (even the new COVID vaccines that gained emergency use authorization were tested in clinical trials on tens of thousands of individuals first, and adverse reactions attributed to the vaccines are exceedingly rare; according to data from the CDC, you’re three times more likely to get struck by lightning than die from a COVID vaccine).7
Brilliant loves keeping anti-vaxx propaganda lying around, especially items from more than a century ago, like the cartoon at the start of this chapter. Such ridiculousness reminds him of how there’s nothing new about the anti-vaxx movement. The distrust of doctors and the government that feeds the anti-vaccination movement might be considered recent, but its roots were put down well over a century ago.8 In the late nineteenth century, tens of thousands of people took to the streets in opposition to compulsory smallpox vaccinations. There were arrests and fines, and people were even sent to jail. Some of the rhetoric that anti-vaxxers used way back then is still employed today, but with greater force now that we have the Internet and social media platforms. People’s soapboxes are bigger and their megaphones are louder. I happened to be working on a documentary about vaccine hesitancy prior to the pandemic, which my team and I fine-tuned and aired in April 2021 (interestingly, in 2019 the World Health Organization named vaccine hesitancy among the top ten threats to global health). When I spoke with Dr. Peter Hotez, a world-renowned virologist, researcher, and outspoken vaccine advocate, he called vaccines “the most powerful technology humankind has ever invented.”9 His group at Baylor College of Medicine produced one of the first SARS vaccines, and he continues to champion vaccine diplomacy—the global partnerships we must create among countries rich and poor to head off major health problems. From his perspective, the anti-vaxx movement of late gained oxygen and moved from the fringes to the mainstream around 2015. The movement was well shaped by targeted messaging, shrewd organization, and strong leadership—something that is not much seen in scientific circles, whose leaders tend to be siloed and usually silent. There is also a lot of money fueling the anti-vaccination movement in the form of books, live events, and medical products. I found it incongruous that many people will consume these products, which haven’t undergone any safety or efficacy testing, but avoid vaccines, which have been through stringent and rigorous medical trials.
For far too long, scientists turned a blind eye to the antiscience folks under the thinking that by not paying attention to them, they’d go away or at least not be heard. But that has changed significantly now that the anti-vaccine community has established a following that perpetuates the disinformation. As much as we celebrate the remarkable science of these new COVID vaccines, their full utility won’t be recognized until enough people take them. Science can rescue us only if we do our part.
The title of this wood engraving by Sir E. L. Sambourne (1898) and owned by the Wellcome Collection in London is “Death as a Skeletal Figure Wielding a Scythe: Representing Fears concerning the Vaccination Act 1898, Which Removed Penalties for Not Vaccinating against Smallpox.” The act had originally forced vaccination but introduced a clause allowing people to opt out for moral reasons. It was the first time “conscientious objection” was recognized in UK law. The growth of anti-vaccination sentiment reached full force in the 1890s with the National Anti-Vaccination League. The group organized protests and produced its own publications to distribute anti-vaccine propaganda. In this artwork, Death, adorned in a cloak and laurel wreath, is brandishing a roll of paper labeled “Bill” and “Anti vaccination.” A coiled snake, an hourglass, and the Lancet medical journal are scattered around the skeletal figure. SOURCE: THE WELLCOME COLLECTION, LONDON.
The whole point of a vaccine is to teach the immune system what that pathogen—a virus, bacterium, fungus, or parasite—looks like. It gives the immune system a giant WANTED sign with the list of names and identifying details of the bad guys to look out for and attack if they show up. This can be done in several ways: inactivated vaccines, live-attenuated vaccines, toxoid vaccines, subunit/recombinant/conjugate vaccines, viral vector vaccines, and the newly developed messenger RNA (mRNA) vaccines.10
Inactivated vaccines do not contain live viruses or bacteria, but either whole killed germs or simply parts of these organisms. These microbial parts are DNA, protein, or specific molecules on the germ’s surface. They allow your immune system to identify this as the enemy and obtain advance notice if that pathogen were to invade. Immune system cells then have a memory that allows them to recognize the organism when they next encounter it in order to produce antibodies to fight it. The immune cells remain circulating in your blood on guard, ready to stop an infection in its tracks if your body is later exposed to the real thing. It’s armed and ready long before the invasion. Often these antibodies either don’t loiter in your body for your whole lifetime or aren’t enough to protect you after just one shot, which is why booster immunizations are recommended—for example, for whooping cough and rabies. Inactivated vaccines are also used to protect against hepatitis A and some types of influenza.
The smallpox vaccine was a live-attenuated vaccine. Other live-attenuated vaccines include the measles vaccine, the rotavirus vaccine, the chickenpox vaccine, and the yellow fever vaccine. A toxoid vaccine should not be confused with a “toxin.” A toxoid is merely a form of vaccine that is an inactivated bacterial toxin. Examples include toxoids against diphtheria and tetanus. These types of vaccines enable the body to render the real toxin harmless if it were to show up in the future. Tetanus is exceedingly rare today (fewer than thirty cases per year occur in the United States), and most doctors have never seen a case. Tetanus is not like other infections that can spread between people. It’s a spore-forming soil bacterium and is transmitted by entering an open wound. Its spore can survive on surfaces, like a rusted nail, for long periods, only to start replicating in the unsuspecting person who steps on the nail. The spore produces a toxin that causes powerful and life-threatening muscle contractions, unless, of course, the person has been vaccinated.
Like inactivated whole-cell vaccines, subunit/recombinant/conjugate vaccines contain not live components of a path
ogen but small fragments of its outer surface protein. This is what stimulates a protective immune response. Some examples of subunit/conjugate vaccines are those for hepatitis B, HPV, meningococcal disease, and some for influenza and shingles.
Viral vector vaccines use a modified version of a different virus as a means to deliver protection. For example, the Johnson & Johnson and AstraZeneca vaccines for COVID employ a harmless disabled adenovirus to convey the instructions for making antibodies. The adenovirus, which causes the common cold in activated form, is not at all related to the coronavirus but it triggers the immune system to respond without infecting the person. Viral vector vaccines have been used for Ebola outbreaks and are under study for Zika, flu, and HIV.
The new mRNA COVID vaccines represent a new class of vaccines because of their RNA technology, but the concept is the same: Introduce instructions to the body for making a protein that the immune system will tag as a bad guy so when the real bad guy shows up, the body is ready to effortlessly fight and take care of it (you probably won’t even know it). I should state clearly and firmly that these mRNA vaccines do not contain the live virus that causes COVID. They contain only the code for a small portion of the virus, the spike protein. They do not affect or interact with your DNA whatsoever. In fact, mRNA never enters the nucleus of the cell, which is where our DNA is kept. The cell breaks down and gets rid of the mRNA soon after it is finished using the message.
I like to think of vaccines as language instructors: They teach the human body a new language. If you’re constantly speaking in that language, such as regular exposure to the virus, the immune system gets pretty good at communicating in this new language. As the virus starts to wither away, there’s less conversation in this new language, and every now and then, a refresher course may need to be given in the form of a booster shot. That quickly reminds the body how to fight the virus, especially if it has had a slight wardrobe change since the original strain.
This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals the ultrastructural morphology exhibited by coronaviruses. Note the spikes on the outer surface of the virus, which impart the look of a corona, or crown, surrounding the virion. SOURCE: CDC.
As previously noted, viruses contain a core of genes made of DNA or RNA wrapped in a coat of proteins; in the case of COVID, the virus is RNA based. To make its now iconic spike proteins, the RNA genes of the virus make messenger RNA that then leads to the production of the proteins. An mRNA of a specific structure makes a protein of a distinct structure.11
Again, it is important to remember that mRNA is a message, and in your body at this moment, there are thousands of such messages being delivered. They are messages that disappear or expire quickly like a Snapchat. The vaccine is a message for one particular coronavirus protein, not the dozens of proteins that make up the virus, so there is no way the mRNA could actually lead to the creation of a virus in your own body. For this reason, the antibodies from people who are vaccinated are different from the antibodies from those who have been infected. In those who have been vaccinated, the antibodies are specific to the spike (S) protein, while those who have been infected may also show antibodies to other parts of the virus, such as the nucleocapsid (N) protein. If you have antibodies to both, your immunity is likely from previous infection.
The first steps taken to make mRNA-based vaccines did not occur on day 1 of Operation Warp Speed. It was thirty years ago that scientists began exploring the possibility.12 The question they raised: If you know the exact structure of the mRNA that makes the critical piece of a virus’s protein coat, such as the spike protein of the COVID germ, could you make that mRNA easily and quickly in a lab setting? The concept seemed simple and doable: Manufacture the mRNA that holds the recipe for a certain virus’s protein coat, then inject that mRNA into someone so it travels through the bloodstream and alerts immune system cells, then confers immunity. But it turns out that the feat was not easily achieved.
We first had to learn how to modify mRNA so that it did not produce violent immune system reactions that could be deadly on their own. Once we figured that out, we next had to become proficient in encouraging human cells to not only pick up the mRNA as it passed by in the blood and produced large quantities of the critical piece of protein, but also generate antibodies to the protein. Finally, we had to learn how to enclose the mRNA inside microscopically small capsules to protect it from being destroyed by chemicals in our blood. That’s a highly simplified version of the mRNA lesson plan that scientists executed as they worked to develop these new vaccines. Of course, they’d also come across some unexpected findings along the way, one of them being that mRNA vaccines trigger a stronger type of immunity than traditional vaccines. These new mRNA-based vaccines for COVID have the power to inflict a double whammy against the virus—they stimulate the immune system to make antibodies and immune system killer cells. That’s like possessing two different kinds of ammo just in case one is not as effective.
I had the pleasure of speaking with two of the chief scientists behind the Pfizer/BioNTech mRNA vaccine that was the first to be approved for emergency use by the FDA on December 11, 2020. Of the thousands of conversations I’ve had while reporting on the pandemic, this may have been one of my favorites. Soon after the Chinese released the virus’s genetic code in January, Drs. Uğur Şahin and Özlem Türeci got cracking thousands of miles away in their German laboratory on designing an mRNA vaccine to hit the virus. It’s where they’d been studying mRNA technology for cancer research but could easily pivot to tackle this new challenge. They had all the tools at their disposal as well as the competency and capacity. Previously, no new vaccine had been developed in less than four years. The race was on, though, with a raging pandemic that could not wait at least four years.
Şahin and Türeci are a married couple with Turkish roots who founded BioNTech in Germany in 2008; their love for each other is matched by their love for science and medicine: After their wedding ceremony in 2002, they immediately went back to their lab to work. “Translating science into survival was what we shared and why at some point we decided to do this journey together of translating science into drugs and vaccines,” Şahin said.
As doctors who specialize in cancer treatments, they described for me “the sense of urgency that cancer brings to people’s lives.” And when Şahin read an article in the Lancet in January about the quickly spreading coronavirus in China, his gut instinct told him that a full-blown pandemic was upon us. Vacation plans at the company were canceled and Project Lightspeed was born.
Soon after they identified several promising vaccine candidates, they needed help testing them and bringing them to market. By March, they forged a relationship with Pfizer, and that “beautiful friendship and collaboration,” as they described it, resulted in the world’s first effective and safe COVID vaccine. Pfizer took no federal money from Trump’s Operation Warp Speed to research and develop a vaccine but did land a supply contract to provide millions of doses. It was a big gamble with no guarantees, but one that ultimately paid off.
It’s important to reiterate that these new breakthrough vaccines are built on many previous breakthroughs and innovations, from biological ones like understanding the structure and function of DNA and its mRNA offspring to purely technological ones such as the ability to transmit large bundles of information (e.g., sequencing data) around the world in seconds. Şahin describes some of the biology in elegant terms, referring to mRNA as the most fundamental way to transfer knowledge to cells. He calls mRNA an intracellular information molecule—the first biomolecule in life invented by nature to enable proteins to be produced based on a grand plan mastered in the DNA. It helps to think of DNA as the hard copy information and mRNA as the soft copy of this information to tell cells what to do next. As its name implies, mRNA are truly messengers—the body’s couriers.
Already, mRNA technologies have been tested to treat sickle cell disease, and they are also being tested for use aga
inst infectious agents such as Ebola, Zika virus, rabies, cytomegalovirus (CMV is a common herpes virus), and influenza. Şahin and Türeci expect the technology to revolutionize many areas of medicine, including cancer treatments and genetic diseases like cystic fibrosis, where mRNA technology could produce vital proteins that are missing in an individual. Even cancer cells make proteins that can be targeted by mRNA vaccines, though this is a more difficult challenge. For starters, not all cancers are the same. What makes curing cancer such an ambitious feat is the heterogeneity of the disease: Within a single cancerous colony of cells, for example, you have a diversity of cells with different markers. And cancers between different individuals are also unique. So imagine being able to personalize cancer treatment with an mRNA vaccine that can be designed to target those unique cancer cells. You figure out the molecular makeup of an individual’s cancer, extract the information, and select the markers against which to use a custom-tailored mRNA vaccine. The versatility and speed with which you can perform this exercise using mRNA technology is breathtaking and potentially limitless.
Şahin and Türeci’s success story has made them wealthy billions of dollars over, but they don’t seem to have changed their lives much as a result. They continue to live with their teenage daughter in a modest apartment near their office. They don’t even own a car; they ride bicycles to work. One of their star biochemists who was among the masterminds of mRNA technology, Hungarian-born researcher Katalin Karikó, also recalls the decades of adversity toiling in the lab and enduring serial demotions in academia. She and her longtime collaborator, immunologist Dr. Drew Weissman, figured out how to make the mRNA technology work. Karikó is a senior vice president at BioNTech overseeing its mRNA work now, having moved there from the University of Pennsylvania in 2013 when the school determined that she was “not of faculty quality.”13 The one thing she does struggle with today is comprehending the fact that her forty years of research are poised to change the lives of billions around the world.
